The present invention relates to cationic bis urea compounds as effective antimicrobial agents, and more specifically to amphiphilic urea compounds capable of self-assembling by non-covalent interactions in water into nanoparticles having potent antimicrobial properties, particularly against fungi.
The number of opportunistic fungal infection cases is increasing due to growing populations of immunocompromised patients (Nat. Reviews-Drug Discovery 2010, 9, 719-727). These invasive infections are mainly caused by Candida and Aspergillus species as well as Cryptococcus neoformans. Candidiasis is a fungal infection of any of the Candida species, among which Candida albicans is the most common. It was reported that candidiasis is the third to fourth most common blood stream infection in the United States. Fungal infections resistant to conventional antifungal drugs are increasing (Nat. Reviews-Microbiology 2005, 3, 547-556; Nat. Reviews-Microbiology 2008, 6, 187-198). Many current antifungal agents (e.g., triazoles and polyenes) have developed resistance in patients (Nat. Reviews-Drug Discovery 2010, 9, 719-727), causing concern in healthcare and clinical settings as the availability of antifungal agents becomes more limited.
Due to their metabolic similarity to mammalian cells, fungi present limited specific targets for therapeutic treatments. For example, amphotericin B exhibits broad-spectrum antimicrobial activity. Amphotericin B binds ergosterol, a key sterol in the fungal membrane, to form aggregates. The aggregates induce pores in the membrane causing cell lysis. On the other hand, amphotericin B can also bind cholesterol in mammalian cell membrane, leading to non-specific toxic side-effects in healthy cells. Hemolysis and nephrotoxicity are commonly reported side-effects caused by this drug in patients.
Host defense peptides and synthetic polymers are two classes of macromolecules currently being studied as effective antimicrobials. These cationic amphiphilic materials can selectively interact with negatively-charged microbial walls or membranes via electrostatic interaction and insertion into membrane lipid domains, causing disintegration of the microbe without harming mammalian cells. In this instance, microbial resistance is less of a concern because microbes cannot easily repair a physically damaged cell wall or membrane.
However, peptides and synthetic polymers have limited clinical applications due to several inherent drawbacks. Antimicrobial peptides are expensive to produce and generally have a short half-life in vivo due to enzymatic degradation. Bio-inspired synthetic polymers are limited by biocompatibility and/or biodegradability for in vivo applications. Although relatively narrow molecular weight distributions of synthetic polymers have been reported (polydispersity index (PDI) of ˜1.1-1.2), individual molecular weight fractions of a polydisperse system are expected to exhibit distinct pharmacological activities in vivo.
The increased prevalence of resistant fungi infections has established an urgent need for innovative materials for treatments.